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1. The Na+ and Cl- transport systems of human erythrocytes have been compared for their sensitivities to diuretics known to act in the ascending limb of Henle's loop. In addition, chemical analogues of 'loop' compounds and also diuretics which act in other areas of the nephron have been examined. 2. The Na+ transport system lacks specificity with respect to inhibition by 'loop' diuretics and also a related chemical analogue studied at equivalent concentrations. 3. The Cl- transport system is inhibited, at low concentrations, by diuretics known to act in the ascending limb of Henle's loop. 4. Erythrocyte Cl- transport offers a useful model with which to study the biochemical action of diuretics.

Urinary clearance techniques have been employed to compare the renal sites of action of three phenoxyacetic acid diuretics in man: ethacrynic (etacrynic) acid and the two enantiomers of indacrinone (MK-196). The effects of these compounds on fractional free-water clearance and reabsorption during maximal hydration and hydropenia, respectively, indicate that whilst ethacrynic acid and (-)-indacrinone have their natriuretic site of action in the medullary portion of the thick ascending limb of Henle's Loop, the (+)-enantiomer of indacrinone acts in the 'cortical diluting segment' or early distal tubule. The natriuretic potencies of all three agents are different as is their effect on the renal handling of uric acid. Ethacrynic acid produces minor urate retention whilst both enantiomers of indacrinone produce uricosuria and hypouricaemia. The apparent difference in the renal sites of action of the enantiomers of indacrinone is discussed in relation to our current knowledge of stereo-selectivity in other pharmacological systems.

1 The renal action of indacrinone (MK-196), a phenoxyacetic acid derivative with diuretic and uricosuric properties, has been studied in fifteen male subjects. 2 Increasing single doses of up to 60 mg of oral indacrinone produced a linear increase in urinary volume and excretion of Na+ and Cl-, whilst the responses of urinary K+, Ca2+, Mg2+ and uric acid excretion, rose to a plateau at the 40 mg dose. 3 Indacrinone evoked a rapid diuretic response which reached a maximum of 2-4 h and was largely complete at 8-12 h after administration. 4 During maximal hydration, indacrinone produced a substantial fall in fractional free water clearance (CH2O), from 8.89% to 5.83% of the filtered load of water, associated with an increase in osmolal clearance, from 1.38% to 5.78% of the filtered load of solute. The reduction in CH2O was of the same order as that produced by a dose of ethacrynic acid with comparable saluretic activity and significantly greater than that produced by an equi-saluretic dose of hydrochlorothiazide. These findings imply an action of indacrinone upon solute transport in the diluting segments of the distal tubule. 5 At the time of maximal indacrinone-induced saluresis, which amounted to an increase from 0.48% to 4.61% of the filtered load of NaCl, fractional urate clearance increased from 5.16% to 12.24% of the filtered load of uric acid. 6 Indacrinone is a long acting diuretic, sharing some properties in common with both loop diuretics and benzothiadiazines. The results are discussed in relation to structure-activity amongst derivatives of phenoxyacetic acid.

Thirty-nine clearance studies were performed in 17 healthy subjects under conditions of maximal hydration or hydropenia to compare the effects on renal solute and water handling of three sulfamoylbenzoic acid derivatives-piretanide, bumetanide, and furosemide-and the phenoxyacetic acid diuretic ethacrynic acid. Except for furosemide, which caused a 7% fall in effective renal plasma flow (ERPF), and ethacrynic acid, which reduced both the glomerular filtration rate (16%) and ERPF (23%) during maximal hydration, changes in hemodynamics were insignificant. At peak saluresis piretanide induced a mean reduction of -18.3% +/- 4.9% in fractional free-water clearance during hydration and -73.2% +/- 5.9% in fractional free-water reabsorption during hydropenia. The other sulfamoylbenzoates lowered fractional clearance and reabsorption of free water to similar extents, implying a major site of action within the medullary portion of the ascending limb. Ethacrynic acid reduced fractional free-water clearance to a greater degree than did the sulfamoylbenzoates. The mean reduction in fractional free-water reabsorption after ethacrynic acid (71.4% +/- 8.2%) was of the same order as that caused by the sulfamoylbenzoates. Similar excretory maxima for sodium, chloride, potassium, calcium, and magnesium were achieved for all four diuretics. Except for piretanide under hydropenia, sulfamoylbenzoate action did not change urinary pH. Ethacrynic acid consistently lowered urinary pH. During hydration piretanide induced phosphaturia (35.3% +/- 8.8%) and uricosuria (40.9% +/- 9.1%). Both bumetanide and piretanide increased fractional urate clearance during hydropenia (16.7% +/- 5.6% and 34.2% +/- 10.5%). There were no changes in phosphate or urate excretion after ethacrynic acid. Our data support the view that sulfamoylbenzoate diuretics exert additional effects on proximal tubular segments that are not shared by ethacrynic acid. Renal responses to piretanide most closely resemble those to bumetanide.

The effects of indacrinone (IND) have been investigated in a two part study. First, a total of 36 clearance studies have been performed in 14 healthy volunteers, under conditions of either maximal hydration or hydropenia, to compare the renal sites of action of single oral doses of IND, 20 mg, ethacrynic acid (EA), 100 mg, and hydrochorothiazide (HCTZ), 100 mg. Under conditions of maximal water hydration, IND increased fractional Na+ excretion from a mean of 1.19 +/- 0.05 to 4.93 +/- 0.67% of GFR. This was similar to the response seen with HCTZ, which increased fractional Na+ clearance up to 3.16 +/- 0.17% of GFR; EA increased fractional Na+ excretion up to 14.5 +/- 2.5% of GFR. The mean reduction in fractional free-water clearance (CH2O/GFR X 100%) invoked by IND, (delta = -34.8% of control) was similar to that produced by EA, (delta = -27.2% of control), and by HCTZ, (delta = -26.6% of control). During hydropenia with superimposed mannitol diuresis, both IND and EA caused a fall in fractional free-water reabsorption (TcH2O/GFR X 100%), delta IND = -20.3% of control, delta EA = -70.1% of control. HCTZ produced a significant increase in fractional free-water reabsorption, delta HCTZ = -20.7% of control. In all studies, single doses of IND were both uricosuric and hypouricaemic. Fractional urate excretion increased from a mean 6.7 +/- 0.1 to 15.2 +/- 2.1% of GFR whilst plasma urate concentration fell from a mean of 0.36 +/- 0.03 to 0.34 +/- 0.03 mM (P less than 0.05) within 2-3 h post drug. HCTZ and EA, in single doses, had little effect on urate excretion. In the second part of the study, a total of 16 healthy volunteers received either IND, 10 mg, or HCTZ 50 mg, orally for 8 days, whilst on a diet of controlled electrolyte content. Both drugs were well tolerated by both sets of subjects with no adverse clinical or pathological findings. Both IND and HCTZ caused a significant reduction in weight and standing systolic blood-pressure during the first 48 h of therapy. At the doses administered, IND and HCTZ displayed similar diuretic responses with respect to water, Na+, Cl-, Ca2+ and PO4(3-) excretion. IND produced less kaliuresis than HCTZ during the first treatment day but cumulative K+ loss was similar for both drugs over the eight days of therapy. Fractional urate excretion after IND remained elevated throughout the 8 days of therapy and the subjects remained isouricaemic for 7 days.(ABSTRACT TRUNCATED AT 400 WORDS)